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Deficiency of the heme-catabolizing enzyme, heme oxygenase-1 (HO-1), in\nboth a human patient and transgenic knockout mice leads to an abundance of\ncirculating heme and damage to vascular endothelium. Although heme can be\ndirectly cytotoxic, the present investigations examine the possibility that\nhemoglobin-derived heme and iron might be indirectly toxic through the generation\nof oxidized forms of low-density lipoprotein (LDL). In support, hemoglobin in\nplasma, when oxidized to methemoglobin by oxidants such as leukocyte-derived\nreactive oxygen, causes oxidative modification of LDL. Heme, released from\nmethemoglobin, catalyzes the oxidation of LDL, which in turn induces endothelial \ncytolysis primarily caused by lipid hydroperoxides. Exposure of endothelium to\nsublethal concentrations of this oxidized LDL leads to induction of both HO-1 and\nferritin. Similar endothelial cytotoxicity was caused by LDL isolated from plasma\nof an HO-1-deficient child. Spectral analysis of the child's plasma revealed a\nsubstantial oxidation of plasma hemoglobin to methemoglobin. Iron accumulated in \nthe HO-1-deficient child's LDL and several independent assays revealed oxidative \nmodification of the LDL. We conclude that hemoglobin, when oxidized in plasma,\ncan be indirectly cytotoxic through the generation of oxidized LDL by released\nheme and that, in response, the intracellular defense-HO-1 and ferritin-is\ninduced. These results may be relevant to a variety of disorders-such as renal\nfailure associated with intravascular hemolysis, hemorrhagic injury to the\ncentral nervous system, and, perhaps, atherogenesis-in which hemoglobin-derived\nheme may promote the formation of fatty acid hydroperoxides.", "subjects" : [ { "otype" : "Classification", "mtid" : 12125, "link" : "/api/classification/12125", "label" : "Általános orvostudomány", "published" : true, "snippet" : true }, { "otype" : "Classification", "mtid" : 10545, "link" : "/api/classification/10545", "label" : "Biológiai tudományok", "published" : true, "snippet" : true }, { "otype" : "Classification", "mtid" : 12215, "link" : "/api/classification/12215", "label" : "Klinikai orvostan", "published" : true, "snippet" : true } ], "digital" : null, "printed" : null, "sourceYear" : 2009, "foreignEdition" : true, "foreignLanguage" : true, "fullPublication" : true, "conferencePublication" : false, "nationalOrigin" : true, "missingAuthor" : false, 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